Targeted Anti-leukemic Therapy as Disease-stabilizing Treatment for Acute Myeloid Leukemia Relapse after Allogeneic Stem Cell Transplantation: Will it be Possible to Combine these Strategies with Retransplantation or Donor Lymphocyte Infusions?

Hakon      Reikvam; Astrid      Olsnes Kittang; Guro      Melve; Knut      Anders Mosevoll; Pal      Tore Bentsen; Elisabeth      Ersvaer; Bjorn      Tore Gjertsen; Oystein      Bruserud

Abstract

Allogeneic stem cell transplantation is commonly used in the treatment of high-risk acute myeloid leukemia (AML). This intensive treatment has a high early transplant-related mortality, and an additional significant cause of death in these patients is later AML relapse. Retransplantation can be considered for a minority of patients, but only 10-20% of selected patients then achieve long-term survival. Donor lymphocyte infusion (DLI) has an antileukemic effect, but the effect of this treatment usually lasts for only 3-4 months. A possible strategy to improve the prognosis could be to combine antileukemic T-cell therapy (i.e. DLI) with AML-targeting therapy. Several aspects have to be considered for such approaches: (i) the therapy should have immunomodulatory rather than immunosuppressive effects; (ii) the regimen should have a low hematological toxicity to preserve residual normal bone marrow function; and (iii) the treatment should have a documented antileukemic effect. DLI elicit both graft versus host and graft versus leukemia effects, and could be added to pharmacological treatment. Epigenetic targeting should be considered in these patients because both demethylating agents as well as the histone deacetylase inhibitors have documented antileukemic effects and have a relatively low hematological toxicity. Other drugs to consider are thalidomide, lenalidomide, antiangiogenic agents, tyrosine kinase inhibitors and heat shock protein 90 inhibitors, which all have both antileukemic and immunomodulatory effects. Relatively few clinical studies are available for patients with this high-risk disease. The designs of future clinical trials have to carefully consider the antileukemic and immunomodulatory effects together with the risk of especially hematological toxicity.

Keywords: Allogeneic stem cell transplantation, graft versus host disease, graft versus leukemia, hematologic malignancy, relapse

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